Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate compound which is also known as intedanib (CAS no.: 656247-17-5) has a selective inhibitor activity on the tyrosine-kinase enzymes targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). It is a drug indicated for the treatment of idiopathic pulmonary fibrosis (IPF) and for some types of non-small-cell lung cancer. The enzymes tyrosine kinases are responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs.
WO0127081 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases. One example of the compounds disclosed is methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate.
Crystalline modification of intedanib was described in WO2004013099 which describes intedanib monoethanesulphonate hemihydrate and preparation thereof with valuable pharmacological effect in the treatment of related diseases and excessive or abnormal cell proliferation.
Salts of intedanib prepared with hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, methanesulfonic acid, ethanedisulfuric acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphtalene-1,5-disulfonic acid, citric acid, D- and L-tartaric acid, fumaric acid, maleic acid, L-lactic acid, glycolic acid, glycine, L- and D-malic acid, malonic acid, oxalic acid, succinic acid, gentisic acid, camphoric acid, benzoic acid, mandelic acid, saccharic acid, salicylic acid, L-aspartic acid, ascorbic acid and xinafoic acid are disclosed in WO2007141283. Following WO2012068441 discloses salts of intedanib prepared with formic acid, adipic acid, acetic acid, ethanesulfonic acid and orotic acid.
Many solid pharmaceutical compounds can exist in various crystalline forms regarded as polymorphs and hydrates/solvates having different crystal structures and hence different physico-chemical properties including melting point, solubility, dissolution rate and finally, bioavailability. In order to distinguish the distinct solid phases of a compound several solid state analytical techniques can be used, e.g. X-Ray Powder Diffraction, solid state NMR and Raman spectroscopy, thermoanalytical methods.
Discovery of new solid phases (polymorphs, solvates and hydrates) of an active pharmaceutical compound offers the opportunity to find the appropriate modification having desirable physico-chemical properties and processability and improves the characteristics of the pharmaceutical product. For this reason there is an explicit need for new solid forms (polymorphs, solvates, hydrates) of intedanib and salts thereof especially in the crystalline form.